The Harvard Program in Gene Transfer for Heart, Lung and Blood Disease is composed of a consortium of investigators with multi-disciplinary expertise and a common goal to create an integrated program that will develop novel vectors and gene transfer technologies useful for the treatment of human disease. The ultimate objective is to establish a proactive program that will attract a broad array of Harvard researchers to participate in the research and to utilize the opportunities of gene therapy for human diseases. In this application, we hypothesize that novel, efficient, cell specific in vivo, or ex vivo gene therapy directed at cardiovascular cells can result in sustained, long term prevention or amelioration of atherogenesis, thrombosis, vascular and myocardial cell injury and death: Our strategies are: 1)To develop novel vector systems that yield efficient and stable transduction of genes relevant to a variety of gene therapy applications. This program will focus on new gene transfer technologies for cardiovascular cells. 2)To identify and develop promoters that direct inducible and regulated expression of transgenes in a cell specific manner in selected target cell populations with the heart. 3)To identify and characterize "therapeutic" genes whose product blocks or modifies the pathobiological process thereby preventing or ameliorating CHD. 4)To apply our gene therapeutic strategies to experimental models of CHD to modify atherosclerosis, restenosis, thrombosis, or myocyte apoptosis. The program achieves a balance between the development of new viral vector systems, expression vector designs, and gene transfer treatment strategies. Studies on novel vector system development will focus on fundamental questions of transducing quiescent cells as well as enabling technologies such as the creation of packaging lines necessary to make gene therapy applications feasible. The other research projects will study the biology of specific target genes, their tissue specific promoters and their potential utilization as gene therapeutic strategies for treating the pathophysiology of CHD. These include 1) the generation of thrombo-resistant endothelium; 2) the engineering of endothelium that is resistant to oxidative stress and is capable of producing optimal levels of vasculoprotective molecules such as nitric oxide; 3) the expression of anti-apoptotic genes in the endothelium; 4) the cell specific inhibition of vascular smooth muscle proliferation and phenotypic alterations; and 5) the improvement of cardiac myocyte function and viability. Although our initial focus is primarily on cardiovascular applications, the scope of gene transfer systems investigated through this program will be sufficiently broad to enable application in lung, blood and other diseases.